BMP9-ID1 Signaling Activates HIF-1α and VEGFA Expression to Promote Tumor Angiogenesis in Hepatocellular Carcinoma

by Selleckchem | Oct 15 2023

Since hepatocellular carcinoma (HCC) is a typical hypervascular malignant tumor with poor prognosis, targeting angiogenesis is an important therapeutic strategy for advanced HCC. Involvement of bone morphologic protein 9 (BMP9), a transforming growth factor-beta superfamily member, has recently been reported in the development of liver diseases and angiogenesis. Here, we aimed to elucidate the role of BMP9 signaling in promoting HCC angiogenesis and to assess the antiangiogenic effect of BMP receptor inhibitors in HCC. By analyzing HCC tissue gene expression profiles, we found that BMP9 expression was significantly correlated with angiogenesis-associated genes, including HIF-1α and VEGFR2. In vitro, BMP9 induced HCC cell HIF-1α/VEGFA expression and VEGFA secretion. Silencing of the inhibitor of DNA-binding protein 1 (ID1), a transcription factor targeted by BMP9 signaling, suppressed BMP9-induced HIF-1α/VEGFA expression and VEGFA secretion, resulting in decreased human umbilical vein endothelial cell (HUVEC) lumen formation. BMP receptor inhibitors, which inhibit BMP9-ID1 signaling, suppressed BMP9-induced HIF-1α/VEGFA expression, VEGFA secretion, and HUVEC lumen formation. In vivo, the BMP receptor inhibitor LDN-212854 successfully inhibited HCC tumor growth and angiogenesis by inhibiting BMP9-ID1 signaling. In summary, BMP9-ID1 signaling promotes HCC angiogenesis by activating HIF-1α/VEGFA expression. Thus, targeting BMP9-ID1 signaling could be a pivotal therapeutic option for advanced HCC.

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The provided text describes a study that investigated the role of bone morphogenetic protein 9 (BMP9) signaling in promoting angiogenesis in hepatocellular carcinoma (HCC), a type of liver cancer. Angiogenesis refers to the formation of new blood vessels, which is crucial for tumor growth and progression. The study aimed to understand how BMP9 signaling contributes to HCC angiogenesis and evaluate the potential of BMP receptor inhibitors as antiangiogenic therapies for HCC.

The researchers analyzed gene expression profiles in HCC tissue samples and found a significant correlation between BMP9 expression and genes associated with angiogenesis, including HIF-1α and VEGFR2. In vitro experiments using HCC cells demonstrated that BMP9 stimulated the expression of HIF-1α and VEGFA, as well as the secretion of VEGFA. Silencing the inhibitor of DNA-binding protein 1 (ID1), a transcription factor targeted by BMP9 signaling, reduced BMP9-induced HIF-1α/VEGFA expression and VEGFA secretion, leading to decreased formation of lumens (central cavities) by human umbilical vein endothelial cells (HUVECs), which are involved in angiogenesis.

The study also investigated the effects of BMP receptor inhibitors, which block BMP9-ID1 signaling, on HCC angiogenesis. These inhibitors successfully suppressed BMP9-induced HIF-1α/VEGFA expression, VEGFA secretion, and HUVEC lumen formation in vitro. Furthermore, in an in vivo experiment using an HCC tumor model, the BMP receptor inhibitor LDN-212854 effectively inhibited tumor growth and angiogenesis by targeting BMP9-ID1 signaling.

Based on these findings, the study suggests that BMP9-ID1 signaling plays a role in promoting angiogenesis in HCC by activating HIF-1α/VEGFA expression. Consequently, targeting BMP9-ID1 signaling could be a potential therapeutic approach for advanced HCC, as it demonstrated antiangiogenic effects and inhibited tumor growth in preclinical models. Further research and clinical trials are needed to validate the efficacy and safety of BMP receptor inhibitors as a treatment option for HCC.